A stereoselective formal total synthesis of (+)-hyperaspine via a tandem aza-Michael reaction

Article abstract of DOI:10.1016/j.tetlet.2007.07.184

A stereoselective formal total synthesis of (+)-hyperaspine via a tandem aza-Michael reaction as the key step in good yield is reported.

Full text of DOI:10.1016/j.tetlet.2007.07.184

Tetrahedron Letters 48 (2007) 6924–6927
A stereoselective formal total synthesis of (+)-hyperaspine
via a tandem aza-Michael reactionI
Palakodety Radha Krishna* and A. Sreeshailam
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 June 2007; revised 16 July 2007; accepted 25 July 2007
Available online 1 August 2007
Abstract—A stereoselective formal total synthesis of (+)-hyperaspine via a tandem aza-Michael reaction as the key step in good
yield is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Hyperaspine 1, belongs to the class of ladybird alka-
loids, isolated from Hyperaspia campestris possessing a
unique 3-oxaquinolizidine skeleton.1 These structural
features coupled with an interesting activity profile have
prompted synthetic efforts toward 1.2 Ma and Zhu2a
synthesized (+)-hyperaspine 1 through hydrogenation
of a d-hydroxy-b-ketoester-derived enamine to achieve
the syn chiral amino alcohol, which was later extrapo-
lated to the target compound. Subsequently, Braekman
and co-workers2b achieved the total synthesis and esta-
blished the absolute configuration of 1 starting from a
protected piperidin-4-one. More recently, Commins
and Sahn2c accomplished the total synthesis of 1 by
the addition of a metalloenolate to a chiral, non-racemic
1-acylpyridinium salt. We recently embarked on a
program3 toward the synthesis of piperidine-containing
bio-active natural products, and in this connection,
herein a formal total synthesis of (+)-hyperaspine 1 is
reported, wherein a novel one-pot, double aza-Michael
reaction is utilized as the key reaction for construction
of the important piperidinone ring-skeleton.
Initially, the strategy (Scheme 1) envisioned involved an
intermolecular SN2 reaction of a chiral mesylate, pre-
pared from keto alcohol 4, with benzylamine followed
by conjugate addition to afford the piperidinone core
skeleton 3, which could subsequently be extrapolated
to (+)-hyperaspine 1.
As depicted in Scheme 1, the synthesis started with the
known4 homoallylic alcohol 5. Thus, the hydroxyl of
5 was protected as its PMB ether 6 (NaH/PMBBr/
DMF/rt), which on exposure to osmium tetraoxide
(OsO4/NMO/acetone:water/rt) mediated dihydroxyl-
ation and subsequent oxidative cleavage (NaIO4/
CH2Cl2/rt) of the ensuing diol resulted in an alde-
hyde, which without isolation was quenched with the
acetylenic anion of 1-heptyne (n-BuLi/THF/ꢀ78 °C) to
afford propargylic alcohol 7 (90% over three steps).
Selective reduction of 7 with LAH in THF afforded
allylic alcohol 8 (90%), which was oxidized (Dess–Martin
periodinane/CH2Cl2/rt) to furnish ketone 9 (95%). Next,
selective deprotection of the PMB ether (DDQ/
CH2Cl2:water/rt) resulted in the keto alcohol 4 (95%).
H
N
H
N
O
O
N
Compound 4 was identified as an ideal substrate for SN2
reaction of its corresponding mesylate with benzylamine
followed by an intramolecular aza-Michael addition5 to
afford the piperidinone derivative 3, which could eventu-
ally be transformed into 3-oxaquinolizidine 2. Thus,
mesylation of 4 (MsCl/Et3N/CH2Cl2/ꢀ20 °C–rt) fol-
lowed by in situ treatment with benzylamine resulted
in 3 (90%) as an inseparable mixture of diastereomers.
However, piperidinone 3 was resolved into two oxaquin-
olizidines 2 and 2a upon cyclization (HCHO/MeOH/rt)
in a 3:1 product ratio and 65% combined yield. The two
products isolated were initially thought to be 2 and its
N
H
+
H
O
O
O
O
1
(+)-hyperaspine
1a
Keywords: (+)-Hyperaspine; 3-Oxaquinolizidine skeleton; Chiral allyl-
ation; Dienone; One-pot double aza-Michael addition; Benzylamine.
q IICT Communication No. 070602.
*
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.184

P. Radha Krishna, A. Sreeshailam / Tetrahedron Letters 48 (2007) 6924–6927
6925
a
b
OPMBOBn
OH OBn
5
6
7
9
OH OPMBOBn
c
d
f
O
OPMBOBn
OBn
OH OPMBOBn
8
O
5
e
3
1
N
3
O
OH
OBn
6
4
2
Bn
2,6-trans piperidin-4-one 3
h
i
3
O
syn
HN
OBn
3
O
OBn
10
+
3
O
NH OBn
anti
aza-enone intermediate
H
N
H
O
O
5
8
4a
N
3
O
+
O
1
g
Ref. 2a
3
1 + 1a
2a
2
Scheme 1. Reagents and conditions: (a) NaH, DMF, PMB–Br, 0 °C–rt, 8 h, 85%; (b) (i) cat OSO4, NMO, acetone–water (4:1), 8 h, (ii) NaIO4,
CH2Cl2, rt, 2 h, (iii) 1-heptyne, n-BuLi, THF, ꢀ78 °C, 90% (over three steps); (c) LAH, THF, 0 °C–rt, 90%; (d) DMP, CH2Cl2, 0 °C–rt, 95%; (e)
DDQ, CH2Cl2–H2O (9:1), 95%; (f) Et3N, MsCl, DMAP (cat), ꢀ20 °C, 20 min, BnNH2, 3 h, 90%; (g) (i) 10% Pd–C/H2, MeOH, (ii) 37% aq HCHO,
MeOH, 2 h, 65% (over two steps); (h) Et3N, MsCl, DMAP (cat), CH2Cl2, ꢀ20 °C to 40 °C, 2 h; (i) BnNH2, 3 h, rt.
C8-epimer.2d However, the spectral data of 2a did not
match with the reported values. For instance, the H
NMR spectrum of 2a revealed H-1 at d 4.59 and at d
4.34 as doublets with Jgem = 8.7 Hz, while the C-8
epimer reportedly showed the same protons at d 4.86
Further, the formation of 2:2a in an isomeric ratio of 3:1
and the stereochemical preferential formation could be
explained by considering7 the fact that the first Michael
reaction of dienone 10 with benzylamine was indeed a
regio- and diastereoselective intermolecular aza-Michael
reaction to afford an aza-enone intermediate (syn and
anti, Fig. 1), which on second aza-Michael reaction
(intramolecular) provided the 2,6-disubstituted-trans-
piperidinones as exclusive products. While, the former
regioselective Michael addition can possibly be explained
by 10-membered H-bonding between the ketone and
benzyl ether groups resulting in a diastereomeric ratio
of 3:1 in favor of the requisite isomer; the exclusive
anti-selectivity of the second aza-Michael reaction was
mainly due to less prevalence of steric repulsions due
to the substituents in the transition states (B and D,
Fig. 1).8
1
and d 3.60 as doublets with Jgem = 7.8 Hz. The optical
25
rotation value also differed {2a: ½aꢁD +15.53 (c 0.35,
25
CHCl3) whereas for the C-8 epimer:2d ½aꢁD ꢀ5.1 (c 1.1,
CHCl3)}. Both 2 and 2a did not exhibit Bohlmann
bands in the IR spectrum, thus inferring their existence
as cis-fused ring conformers. Nevertheless the formation
of 2a needed to be rationalized, and could be logistically
explained if a double aza-Michael addition of dienone
10 was envisaged as the intervening reaction to result
initially in 3, which was later converted into 2 and 2a.
This argument was indeed supported by the isolation
of dienone 10 when the mesylation reaction was pro-
longed. Dienone 10 was synthesized by an alternate
route,6 double aza-Michael reaction of which produced
identical results.
The above analysis was found to be in complete agree-
ment with the spectral data of 2 and 2a.9 Thus, the prod-

6926
P. Radha Krishna, A. Sreeshailam / Tetrahedron Letters 48 (2007) 6924–6927
H
steric hindrance
O
BnO
N
BnO
O
O
H
O
X
NBn
Disfavored
NBn
A
BnO
O
HN OBn
O
BnO
O
O
O
H
NBn
N
NBn
B
H
O
syn aza-enone intermediate
2
Favored
H
NBn
NBn
N
X
H
O
O
O
BnO
BnO
C
Disfavored
steric hindrance
OBn
HN
O
NBn
NBn
O
H
anti aza-enone intermediate
O
N
O
BnO
H
BnO
D
O
2a
Favored
Figure 1. Stereoselectivity of the second aza-Michael addition.
2. (a) Zhu, W.; Ma, D. Org. Lett. 2003, 5, 5063–5066; (b)
Dooms, C.; Laurent, P.; Daloze, D.; Pasteels, J.; Nedved,
O.; Braekman, J.-C. Eur. J. Org. Chem. 2005, 1378–
1383; (c) Commins, D.; Sahn, J. J. Org. Lett. 2005, 7,
5227–5228; For an 8-epimer synthesis, please see: (d)
Ma, D.; Zhu, W. Tetrahedron Lett. 2003, 44, 8609–
8612.
3. (a) Radha Krishna, P.; Krishnarao, Lopinti Synlett 2007,
1742–1745; (b) Radha Krishna, P.; Dayaker, G. Unpub-
lished results.
uct profile was rationalized by the regio- and stereoselec-
tive aza-Michael addition of benzylamine at the b-car-
bon of the enone followed by stereospecific
intramolecular aza-Michael addition. The physical and
spectroscopic data of 2 were identical to the reported
25
25
values. ½aꢁD +25.4 (c 0.75, CHCl3); {lit.2a ½aꢁD +21.0 (c
0.67, CHCl3). Hence, the synthesis of 2 reported herein
constitutes a formal synthesis of (+)-hyperaspine 1.
In conclusion, we have disclosed a concise and stereo-
selective formal total synthesis of (+)-hyperaspine 1
through a one-pot double aza-Michael reaction on a chi-
ral enone intermediate. A highly stereocontrolled double
aza-Michael reaction played a crucial role in minimizing
the number of products. The synthesis takes advantage
of the lone stereogenic center of the starting material
in creating the additional chiral centers in a stereode-
fined fashion. A hitherto unreported diastereomeric 3-
oxaquinolizidine 2a was also synthesized through which
an isomer of 1 could be realized. The strategy reported
herein is general and can be adopted for the synthesis
of similar piperidine-4-one systems.
4. Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833–
4835.
5. (a) Perlmutter, P. In Conjugate Addition Reactions in
Organic Synthesis; Baldwin, J. E., Magnus, P. D., Eds.;
Tetrahedron Organic Chemistry Series; Pergamon: Oxford,
1992; Vol. 9; (b) Scha¨fer, M.; Drauz, K.; Schwarm, M. In
Methoden Org. Chem., 4th ed.; Houben-Weyl, 1995; Vol.
E21/5, pp 5588–5642; (c) Enders, D.; Wahl, H.; Bettray, W.
Angew. Chem., Int. Ed. Engl. 1995, 34, 453–457, and
references cited therein.
6. Compound 10 was independently synthesized from the
known ester2d as follows:
OBn
O
OBn
OBn
OH
3. LAH reduction
4. Oxidation
1. DIBAL-H
COOEt
2. n-BuLi, n-heptyne,
10
4
THF, -78 C-rt
4
7. It is logical to think that if the initial aza-Michael reaction
were to occur on the b-carbon of the dienone nearer to the
alkyl substituent the product ratio would have altered to 1:1
in favor of 2 and its C-8 epimer considering that the
exclusive anti-selectivity of the second Michael reaction is
still retained. Since the C-8 epimeric product was never
observed, this argument was discounted.
Acknowledgment
One of the authors (A.S.) thanks CSIR, New Delhi, for
the financial assistance in the form of a fellowship.
8. (a) Yun, H.; Gagnon, A.; Danishefsky, S. J. Tetrahedron
Lett. 2006, 47, 5311–5315; (b) Zou, W.; Sandbhor, M.;
Bhasin, M. J. Org. Chem. 2007, 72, 1226–1234.
References and notes
9. Spectral data of selected compounds: Compound 2a: color-
1. Lebrun, B.; Braekman, J.-C.; Daloze, D.; Kalushkov, P.;
25
1
less oil; ½aꢁD +15.53 (c 0.35, CHCl3); H NMR (200 MHz,
Pasteels, J. M. Tetrahedron Lett. 2001, 42, 4621–4623.

P. Radha Krishna, A. Sreeshailam / Tetrahedron Letters 48 (2007) 6924–6927
6927
CDCl3): d 4.59 (d, J = 8.7 Hz, 1H), 4.34 (d, J = 8.7 Hz,
1H), 3.95–3.77 (m, 1H), 3.62–3.47 (m, 1H), 3.27–3.11 (m,
1H), 2.63 (dd, J = 13.8, 10.1 Hz, 1H), 2.43 (dd, J = 14.2,
6.5 Hz, 1H), 2.22–2.09 (m, 2H), 1.75–1.15 (m, 13H), 0.88 (t,
J = 6.5 Hz, 3H); FTIR (neat): 2941, 2854, 1715 cmꢀ1; MS
1236, 1098 cmꢀ1; MS ESI 240 (M+1); Anal. Calcd for
C14H25NO2: C, 70.25; H, 10.53; N, 5.85. Found: C, 70.21;
25
H, 10.51; N, 5.79. Compound 4: colorless oil; ½aꢁD +10.7 (c
1
1.0, CHCl3); H NMR (300 MHz, CDCl3): d 7.32–7.19 (m,
5H, Ar–H), 6.85–6.72 (m, 1H), 6.05 (d, J = 15.8 Hz, 1H),
4.59 (d, J = 11.3 Hz, 1H), 4.43 (d, J = 11.3 Hz, 1H), 4.33–
4.24 (m, 1H), 3.89–3.79 (m, 1H), 2.63 (dd, J = 7.9, 3.7 Hz,
2H), 2.24–2.13 (m, 2H), 1.5 (dt, J = 7.9, 3.3 Hz, 2H), 1.33–
1.22 (m, 9H), 0.90 (t, J = 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 13.91, 19.65, 22.54, 27.64, 31.29, 32.44, 43.37,
46.35, 65.12, 70.82, 72.15, 127.54, 127.78, 128.35, 130.52,
138.80, 149.09, 201.04; IR (neat): 3400, 3050, 1710, 1605,
1120 cmꢀ1; LC–MS 341.3 (M+Na)+; Anal. Calcd for
C20H30O3: C, 75.43; H, 9.50. Found: C, 75.27; H, 9.68.
25
ESI 240 (M++1). Compound 2: colorless oil; ½aꢁD +25.4 (c
0.75, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.73 (d,
J = 10.5 Hz, 1H), 4.24 (d, J = 10.5 Hz, 1H), 3.63 (m, 1H),
3.48 (m, 1H), 3.36 (m, 1H), 2.68 (ddd, J = 14.0, 6.4, 1.2 Hz,
1H), 2.48–2.26 (m, 2H), 2.16 (ddd, J = 13.9, 4.5, 1.8 Hz,
1H), 1.63–1.20 (m, 10H), 1.18 (d, J = 6.4 Hz, 3H), 0.88
(t, J = 6.5 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 14.0,
21.5, 22.5, 24.6, 30.8, 31.9, 35.7, 45.5, 46.9, 53.2, 56.3,
73.5, 81.1, 209.0; FTIR (neat): 2945, 2861, 1722, 1350,